Carvedilol for the Prevention of Anthracycline/Anti-HER2 Therapy Associated Cardiotoxicity Among Women With HER2-Positive Breast Cancer Using Myocardial Strain Imaging for Early Risk Stratification
Study Details
Study Description
Brief Summary
The purpose of this study is to find out the effects, good and/or bad, of a beta blocker (carvedilol) on heart function during treatment with anti-HER2 medication(s) including trastuzumab (Herceptin).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
This phase II placebo-controlled study will evaluate the effect of carvedilol, compared to placebo, on anthracycline/anti-HER2 therapy induced left ventricular dysfunction in patients with HER2-positive breast cancer who are receiving adjuvant or neoadjuvant therapy. All patients will undergo routine cardiac surveillance with 2D echocardiograms per standard of care at multiple time points which will align as closely as possible to the following: pre-anthracycline (baseline), pre-anti-HER2 therapy, and 3, 6, 9, and 12 months (+/- 4 weeks) after initiation of anti-HER2 therapy. In the case that standard of care echocardiograms are not done at these time points, either due to a delay in anti-cancer therapy or due to the patient's medical condition, the principal investigator will determine if the standard of care echocardiogram may be used in lieu of one of the time points listed. Additional speckle tracking strain analysis will be performed on these echocardiograms, and blood specimens will be drawn at several time points for biomarker analysis.
After completion of anthracycline treatment and prior to initiation of anti-HER2 therapy, 32 patients with abnormal myocardial strain, defined as global longitudinal strain < 19% or % change from baseline by > 11%, will be randomized in a 1:1 ratio to carvedilol versus placebo. Carvedilol will be administered twice daily for approximately 1 year OR until the end of anti-HER2 therapy, if it is discontinued prior to 1 year. Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Carvedilol Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. |
Drug: Carvedilol
|
| Placebo Comparator: placebo Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. |
Other: placebo
|
Outcome Measures
Primary Outcome Measures
- Maximum Change in LVEF at 3 Months [3 months]
Value at 3 months minus value at baseline
- Maximum Change in LVEF at 6 Months [6 months]
Value at 6 months minus value at baseline
- Maximum Change in LVEF at 9 Months [9 months]
Value at 9 months minus value at baseline
- Maximum Change in LVEF at 12 Months [12 months]
Value at 12 months minus value at baseline
Secondary Outcome Measures
- Incidence of Abnormal LVEF at 12 Months [12 months]
The study is designed to detect an intergroup difference of absolute difference of 10 percentage points (simple difference) in the change in LVEF between the experimental and control group. Ten percent is the change in LVEF that is associated with differing degrees of left ventricular dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ among groups of patients who have LVEF differing by 10%.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Female
-
Age ≥ 18 years
-
Non-metastatic histologically confirmed primary invasive breast carcinoma
-
Pathologically confirmed HER2-positive breast cancer
-
Scheduled to receive anthracycline chemotherapy followed by anti-HER2 therapy at MSKCC
-
Able and willing to provide informed consent
-
Willing and able to comply with the requirements of the protocol
-
Able to swallow capsules
For Aim 2, all patients must meet the following criteria:
-
Meet all inclusion criteria above
-
LVEF > 50%
-
Abnormal global longitudinal strain (<19%, or a % decrease of ≥ 11% from baseline) prior to initiation of planned anti-HER2 therapy
-
Heart rate ≥ 50 beats per minute
-
Sitting systolic blood pressure > 90 mmHg
Exclusion Criteria:
-
Patients are to be excluded from randomization for Aim 2 of this study if they meet any of the following criteria:
-
Current treatment with ACE-inhibitors or beta blockers
-
Allergies or inability to tolerate beta blockers previously due to bradycardia, hypotension, or AV block.
-
Known history of NCI CTCAE (Version 4.0) Grade ≥ 2 symptomatic CHF, myocardial infarction within 12 months prior to randomization, significant symptoms (Grade ≥ 3) relating to left ventricular dysfunction, significant (moderate or severe) valvular disease, or significant cardiac arrhythmia (Grade ≥ 3)
-
Pre-menopausal women without a negative serum or urine pregnancy test within 4 weeks of starting treatment
-
Enrollment in a therapeutic intervention trial in the Breast Medicine service
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Memorial Sloan Kettering West Harrison | Harrison | New York | United States | 10604 |
| 2 | Memorial Sloan Kettering Cancer Center | New York | New York | United States | 10065 |
Sponsors and Collaborators
- Memorial Sloan Kettering Cancer Center
Investigators
- Principal Investigator: Anthony Yu, MD, Memorial Sloan Kettering Cancer Center
Study Documents (Full-Text)
More Information
Additional Information:
Publications
None provided.- 14-099
Study Results
Participant Flow
| Recruitment Details | |
|---|---|
| Pre-assignment Detail | 11 participants were randomized to treatment. 71 participants were not randomized to treatment. |
| Arm/Group Title | Carvedilol | Placebo |
|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo |
| Period Title: Overall Study | ||
| STARTED | 5 | 6 |
| COMPLETED | 4 | 6 |
| NOT COMPLETED | 1 | 0 |
Baseline Characteristics
| Arm/Group Title | Carvedilol | Placebo | Total |
|---|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo | Total of all reporting groups |
| Overall Participants | 5 | 6 | 11 |
| Age (years) [Mean (Full Range) ] | |||
| Mean (Full Range) [years] |
45.6
|
55.2
|
50.8
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
5
100%
|
6
100%
|
11
100%
|
| Male |
0
0%
|
0
0%
|
0
0%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
1
20%
|
0
0%
|
1
9.1%
|
| Not Hispanic or Latino |
4
80%
|
6
100%
|
10
90.9%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
2
33.3%
|
2
18.2%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
20%
|
1
16.7%
|
2
18.2%
|
| White |
2
40%
|
3
50%
|
5
45.5%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
2
40%
|
0
0%
|
2
18.2%
|
| Region of Enrollment (Count of Participants) | |||
| United States |
5
100%
|
6
100%
|
11
100%
|
Outcome Measures
| Title | Maximum Change in LVEF at 3 Months |
|---|---|
| Description | Value at 3 months minus value at baseline |
| Time Frame | 3 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Carvedilol | Placebo |
|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo |
| Measure Participants | 5 | 6 |
| Median (Full Range) [change in percent ejection fraction] |
1
|
-5
|
| Title | Maximum Change in LVEF at 6 Months |
|---|---|
| Description | Value at 6 months minus value at baseline |
| Time Frame | 6 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Carvedilol | Placebo |
|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo |
| Measure Participants | 5 | 6 |
| Median (Full Range) [change in percent ejection fraction] |
-2
|
-5
|
| Title | Maximum Change in LVEF at 9 Months |
|---|---|
| Description | Value at 9 months minus value at baseline |
| Time Frame | 9 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Carvedilol | Placebo |
|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo |
| Measure Participants | 5 | 6 |
| Median (Full Range) [change in percent ejection fraction] |
-3.5
|
-5.5
|
| Title | Maximum Change in LVEF at 12 Months |
|---|---|
| Description | Value at 12 months minus value at baseline |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Carvedilol | Placebo |
|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo |
| Measure Participants | 5 | 6 |
| Median (Full Range) [change in percent ejection fraction] |
-2.5
|
-2
|
| Title | Incidence of Abnormal LVEF at 12 Months |
|---|---|
| Description | The study is designed to detect an intergroup difference of absolute difference of 10 percentage points (simple difference) in the change in LVEF between the experimental and control group. Ten percent is the change in LVEF that is associated with differing degrees of left ventricular dysfunction, and long-term studies among non-cancer patients have shown that outcomes differ among groups of patients who have LVEF differing by 10%. |
| Time Frame | 12 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| [Not Specified] |
| Arm/Group Title | Carvedilol | Placebo |
|---|---|---|
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo |
| Measure Participants | 5 | 6 |
| Abnormal LVEF |
2
40%
|
1
16.7%
|
| Normal LVEF |
3
60%
|
5
83.3%
|
Adverse Events
| Time Frame | 12 months | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Carvedilol | Placebo | ||
| Arm/Group Description | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. Carvedilol | Treatment in both carvedilol and placebo groups will be systematically up-titrated at weeks 3, 6, and 9 (+/- 1 week) after randomization to a goal dose of 25mg twice daily. placebo | ||
All Cause Mortality |
||||
| Carvedilol | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/5 (0%) | 0/6 (0%) | ||
Serious Adverse Events |
||||
| Carvedilol | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 1/5 (20%) | 0/6 (0%) | ||
| Infections and infestations | ||||
| Skin infection | 1/5 (20%) | 0/6 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Carvedilol | Placebo | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/5 (100%) | 6/6 (100%) | ||
| Blood and lymphatic system disorders | ||||
| Anemia | 5/5 (100%) | 6/6 (100%) | ||
| Investigations | ||||
| Alanine aminotransferase increased | 3/5 (60%) | 1/6 (16.7%) | ||
| Alkaline phosphatase increased | 4/5 (80%) | 0/6 (0%) | ||
| Aspartate aminotransferase increased | 2/5 (40%) | 2/6 (33.3%) | ||
| Blood bilirubin increased | 1/5 (20%) | 0/6 (0%) | ||
| Neutrophil count decreased | 0/5 (0%) | 2/6 (33.3%) | ||
| Lymphocyte count decreased | 2/5 (40%) | 2/6 (33.3%) | ||
| Platelet count decreased | 2/5 (40%) | 2/6 (33.3%) | ||
| White blood cell decreased | 2/5 (40%) | 3/6 (50%) | ||
| Metabolism and nutrition disorders | ||||
| Hypernatremia | 1/5 (20%) | 0/6 (0%) | ||
| Hyperglycemia | 3/5 (60%) | 4/6 (66.7%) | ||
| Hypoalbuminemia | 2/5 (40%) | 2/6 (33.3%) | ||
| Hypoglycemia | 1/5 (20%) | 0/6 (0%) | ||
| Hypokalemia | 0/5 (0%) | 1/6 (16.7%) | ||
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Dr. Anthony Yu, MD |
|---|---|
| Organization | Memorial Sloan Kettering Cancer Center |
| Phone | 212-639-7932 |
| yua3@mskcc.org |
- 14-099